Fibroblast growth factor-23 abolishes 1,25-dihydroxyvitamin D₃-enhanced duodenal calcium transport in male mice

Abstract

Herein, we demonstrated by Ussing chamber technique that male mice administered 1 g/kg 1,25(OH) 2D3 sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1-4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH) 2D3-induced calcium absorption in the duodenal tissues taken from the 1,25(OH) 2D3-treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH) 2D3 preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH) 2D3-induced upregulation of TRPV5, TRPV6, and calbindin-D 9k, but not PMCA1b expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH) 2D3-induced calcium absorption.calbindin-D 9k; fibroblast growth factor receptor; Klotho; transient receptor potential vanilloid type 6; Ussing chamber FIBROBLAST GROWTH FACTOR (FGF)-23 has been recognized as the osteoblast/osteocyte-derived phosphate-regulating hormone, a phosphatonin with phosphaturic and hypophosphatemic action (19,42,45 (29). Some hereditary and acquired diseases, e.g., autosomal dominant hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and X-linked hypophosphatemic rickets, result from abnormally high circulating FGF-23 activity. Dysregulation of FGF-23 action is also evident in various pathological conditions, such as chronic metabolic acidosis and chronic kidney disease (11,20).Once secreted from osteoblasts and osteocytes, FGF-23 exerts its phosphaturic action in the renal proximal tubular cells via the FGF receptor (FGFR)/Klotho coreceptor complex, thereby downregulating Na ϩ -dependent phosphate transporter (NPT)-2a and NPT-2c expression (14). Its intracellular signaling in renal epithelial cells is conveyed through a number of pathways, e.g., mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), p38 MAPK, phosphoinositide 3-kinase (PI3K)/Akt, and protein kinase C (PKC) (12,13,43). FGF-23 also downregulates renal 25-hydroxyvitamin D 1␣-hydroxylase (1-OHase; also known as Cyp27b1) and upregulates 24-hydroxylase (24-OHase, Cyp24a1), which are important enzymes for production and inactivation of 1,25(OH) 2 D 3 , respectively, thereby reducing circulating levels of 1,25(OH) 2 D 3 (35, 42). Since 1,25(OH) 2 D 3 is the cardinal regulator of intestinal cal...

Hepcidin and 1,25(OH)2D3effectively restore Ca2+transport in β-thalassemic mice: reciprocal phenomenon of Fe2+and Ca2+absorption

“…In WT mice, the duodenum was well responsive to 3-day injection of 1 or 2 g/kg 1,25(OH) 2 D 3 , which were the conventional 1,25(OH) 2 D 3 regimens for stimulation of the active calcium absorption (22). However, despite no change in VDR expression (5), the duodenal calcium transport in BKO mice did not respond to the conventional 1,25(OH) 2 D 3 regimen.…”

“…Transepithelial calcium fluxes were determined as described previously (19,22). Briefly, the tissue was first equilibrated in the chamber with physiological bathing solution for 10 min.…”

“…Besides the transcellular pathway, there is the paracellular calcium transport that is dependent on luminal calcium concentration, i.e., the higher the luminal concentration, the greater the paracellular calcium flux (19). In rodents, both mechanisms of calcium transport are markedly stimulated by 3-day subcutaneous injection of 1,25(OH) 2 D 3 (22,23). This is because the functions of most calcium transporters, particularly TRPV6, NCX1, and PMCA 1b , are 1,25(OH) 2 D 3 dependent (46).…”

Ultraviolet B activated 1,25(OH)₂D affects the level of fibroblast growth factor-23 in human

“…Table 1 showed the baseline characteristics of study participants. The mean age of the 10 subjects (7 men and 3 women) was 27.9 years (range: [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] …”

“…Meanwhile, the levels of 1,25(OH) 2 D declined to the baseline levels in time points of 8th and 12th week when the level of FGF-23 peaked. As one of feedback mechanism, FGF-23 has inhibitory action on 1-alpha hydroxylase to prevent further production of 1,25(OH) 2 D, so these recovery pattern in 1,25(OH) 2 D levels might also have been caused by increased FGF-23 levels [23].…”